A Tangier liver cDNA library was established in E. coli and two apoA-I cDNA clones were identified. Nucleic acid sequence analysis of these clones shown amino acid sequence 116-243 encoded by Tangier mRNA is identical to normal except at position 120 where there is one base change (G-T), thus changing glutamic acid at 120 to aspartic acid. This base substitution also creates a new Sau3A1 restriction site. The importance of this amino acid substitution is currently underway. In collaboration with Drs. A. Sakaguchi and S. Naylor, we have used the cloned apoA-I cDNA as hybridization probe in Southern blot assay of human-mouse somatic cells hybrid DNA to localize the apoA-I and apoC-III gene to the p11-q13 region of human chromosome 11. The study represents the first definitive assignment of an apolipoprotein gene to human chromosome. In a separate Southern blot analysis, we identified genetic differences in kindreds with apoA-I and apoC-III deficiency. Two additional apolipoproteins, A-II and C-II, have been cloned. Nucleic acid sequence analysis showed these apoproteins are initially synthesized as precursor proteins. Apolipoprotein A-II is initially synthesized as preproapo A-II with a 23 amino acid preprosequence. PreproapoA-II then undergoes co-translational and post-translational cleavage to mature 77 amino acid long apoA-II. Apolipoprotein C-II is initially synthesized as preapoC-II with a 22 amino acid presequence. PreapoC-II then undergoes co-translational cleavage to mature 79 amino acid long apoC-II.